Treatment of narcolepsy: A rare disease of unknown etiology

Background: Narcolepsy, also known as Gélineau syndrome, is a chronic and neurological disease that affects 0.05% of the European population, though that percentage could be higher due to the diagnostic difficulties. The main symptom is excessive daytime sleepiness, although it may be accompanied by cataplexy, sleep paralysis and hypnagogic hallucinations. Objective: Nowadays, there is no cure for narcolepsy and the treatment is symptomatic: psychostimulants for the sleepiness by means of amphetamines, methylphenidate or modafinil, and antidepressants and sodium oxybate for treating cataplexy. Method: This is a short review regarding pharmacotherapy for narcolepsy. Result: Hypocretins were discovered in 1998. They are neuropeptides whose deficit is responsible for this symptomatology, has opened up a new field of investigation. Conclusion: Agonists of hypocretins could be a promising therapy against this disease.

Narcolepsy with Cataplexy: What we know about it in 2021

Narcolepsy is a model disease for many sleep-wake disorders, a dyssomnia. Diagnostically important is the so-called “narcoleptic tetrad”: Daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Common differential diagnoses are epilepsy, psychoses, pharmacological influences and sleep disorders. The correct diagnosis is often made too late. Often, negative psychosocial consequences of narcolepsy have already occurred for the patients in the meantime, which can be prevented by an early diagnosis. Therefore, the objective of this White Paper is to raise more awareness in the medical community.

0428 Taiep Rats Had Normal Levels of Orexin Neurons in the Lateral Hypothalamus But Their Cataplexy Attacks are Sensible to Specific Orexin B Agonist

Introduction Narcolepsy is characterized by sleep fragmentation, sleep paralysis, hypnagogic hallucinations and cataplexy. The cataplexy is a sudden loss of muscle tone triggered by emotions in humans, as well as in animal models. It is stablished that most of the patients had a significant decrease of orexin neurons in the lateral hypothalamus. Taiep rats had a mutation in tubulin TUBB4A and suffer immobility episodes (IE′s) that had a desynchronized activity in the cortex associated with theta rhythm in the hippocampus similar to narcolepsy patients. The aim of this study was to analyze the effects of central administration of an orexin B agonist and determination by immunohistochemistry of the number of orexin neurons on adult male taiep rats. Methods We used 14 male taiep rats of 9 months of age. The subjects (Ss) lived 3-4 in acrylic cages with water and food pellets ad libitum, under a 12:12 light-dark cycle (lights on at 0700), whit-controlled temperature and humidity in the recording room. All Ss were implanted to record EEG, EMG and EOG to characterize immobility episodes (IE′s) in a control 8 h recording and after i.c.v. administration of [Ala 11, D-Leu 15]-orexin B with 1, 3 and 10 nmol/1 μL. We measured the number, mean duration and latency to the first IE′s. Results The administration of [Ala 11, D-Leu 15]-orexin B significantly reduced the number of IE′s (P<0.01), from 4.28 ± 1.5 IE′s to just 0.25 ± 0.17 with 10 nmol/1 μL dose, but did not change the amount of awakening, slow wave or rapid eye movement sleep. Importantly, the number or orexins neurons were similar between taiep and Sprague-Dawley rats. Conclusion The myelin mutant taiep rats is a model of narcolepsy with cataplexy with normal number of orexin neurons in the lateral hypothalamus. Additionally, a specific orexin B agonist reduced IE′s without any effect the sleep pattern. This could be useful for the design of new treatments. Support CONACYT grants 243333 and 243247 to CC and JRE, respectively. Grants from VIEP-BUAP 2019 and CA in Neuroendocrinología BUAP-CA-288.

0427 Bicuculine Increased the Cataplexy in the Male Taiep Rats: An Animal Model of Narcolepsy with an Inherent Tubulopathy

Introduction Narcolepsy is a hypersomnolence that is characterized by sleep fragmentation, sleep paralysis, hypnagogic hallucinations and cataplexy that is characterized by atonia induced by strong emotions. The amygdala is the trigger for cataplexy through GABAergic mechanisms. Taiep is a myelin mutant with TUBB4A tubulopathy which showed spontaneous episodes of atonia or induced by manipulations from the tail or the thorax. EEG recordings during immobility episodes (IE′s) had a cerebral cortex desynchronized associated to theta rhythm in the hippocampus. The aim of this sturdy was to analyze the effects of bicuculine administration on IE′s and sleep-wake pattern on adult male taiep rats. Methods We used 6 taiep male rats at 9 months of age. The subjects (Ss) lived in individual acrylic cages with water and food pellets available ad libitum, under a 12:12 light-dark cycle (lights on at 0700), with controlled temperature and humidity recording room. All Ss were implanted to record EEG, EMG and EOG to characterize EI′s. We evaluated a basal 24 h EEG recording and then after bicuculine i.p. administration of 0.5, 1 y 1.5 mg/Kg every 48h. We measured the number, mean duration and latency to the first IE′s. Results The duration of IE′s increased 527% with 1 mg/Kg and reach 700% with 1.5 mg/Kg of bicuculine (P<0.01) with respect to saline-treated control group. Importantly, the frequency of IEs did not differ among the groups and did not affect the number of awake, slow wave or rapid eye movements sleep phases. Conclusion Bicuculine, a specific GABA antagonist, modify the duration of IES but not their frequency supporting a role of GABAergic mechanism on IE′s. It is relevant because sodium oxybate, an indirect GABA agonist, reduced cataplexy and improved sleep quality on narcoleptic patients. Support CONACYT grants 243333 and 243247 to CC and JRE, respectively and from VIEP-BUAP 2019 to CA in Neuroendocrinología BUAP-CA-288.

HLA and sleep parameter associations in post-H1N1 narcolepsy type 1 patients and first-degree relatives

Study Objectives To explore HLA (human leukocyte antigen) in post-H1N1 narcolepsy type 1 patients (NT1), first-degree relatives and healthy controls, and assess HLA associations with clinical and sleep parameters in patients and first-degree relatives. Methods Ninety post-H1N1 NT1 patients and 202 of their first-degree relatives were HLA-genotyped (next generation sequencing) and phenotyped (semistructured interviews, Stanford Sleep Questionnaire, polysomnography, and multiple sleep latency test). HLA allele distributions were compared between DQB1*06:02-heterozygous individuals (77 patients, 59 parents, 1230 controls). A subsample (74 patients, 114 relatives) was investigated for associations between HLA-loci and continuous sleep variables using logistic regression. Identified candidate HLA-loci were explored for HLA allele associations with hypnagogic hallucinations and sleep paralysis in 90 patients, and patient allele findings were checked for similar associations in 202 relatives. Results DQB1*06:02 heterozygous post-H1N1 NT1 patients (84.4% H1N1-vaccinated) showed several significant HLA associations similar to those reported previously in samples of mainly sporadic NT1, i.e. DQB1*03:01, DRB1*04:01, DRB1*04:02, DRB1*04:07, DRB1*11:04, A*25:01, B*35:03, and B*51:01, and novel associations, i.e. B*14:02, C*01:02, and C*07:01. Parents HLA alleles did not deviate significantly from controls. The HLA-C locus was associated with sleep parameters in patients and relatives. In patients C*02:02 seems to be associated with protective effects against sleep paralysis and hypnagogic hallucinations. Conclusions Our findings of similar risk/protective HLA-alleles in post-H1N1 as in previous studies of mainly sporadic narcolepsy support similar disease mechanisms. We also report novel allelic associations. Associations between HLA-C and sleep parameters were seen independent of NT1 diagnosis, supporting involvement of HLA-C in sleep subphenotypes.

Increased creative thinking in narcolepsy

Some studies suggest a link between creativity and rapid eye movement sleep. Narcolepsy is characterized by falling asleep directly into rapid eye movement sleep, states of dissociated wakefulness and rapid eye movement sleep (cataplexy, hypnagogic hallucinations, sleep paralysis, rapid eye movement sleep behaviour disorder and lucid dreaming) and a high dream recall frequency. Lucid dreaming (the awareness of dreaming while dreaming) has been correlated with creativity. Given their life-long privileged access to rapid eye movement sleep and dreams, we hypothesized that subjects with narcolepsy may have developed high creative abilities. To test this assumption, 185 subjects with narcolepsy and 126 healthy controls were evaluated for their level of creativity with two questionnaires, the Test of Creative Profile and the Creativity Achievement Questionnaire. Creativity was also objectively tested in 30 controls and 30 subjects with narcolepsy using the Evaluation of Potential Creativity test battery, which measures divergent and convergent modes of creative thinking in the graphic and verbal domains, using concrete and abstract problems. Subjects with narcolepsy obtained higher scores than controls on the Test of Creative Profile (mean ± standard deviation: 58.9 ± 9.6 versus 55.1 ± 10, P = 0.001), in the three creative profiles (Innovative, Imaginative and Researcher) and on the Creative Achievement Questionnaire (10.4 ± 25.7 versus 6.4 ± 7.6, P = 0.047). They also performed better than controls on the objective test of creative performance (4.3 ± 1.5 versus 3.7 ± 1.4; P = 0.009). Most symptoms of narcolepsy (including sleepiness, hypnagogic hallucinations, sleep paralysis, lucid dreaming, and rapid eye movement sleep behaviour disorder, but not cataplexy) were associated with higher scores on the Test of Creative Profile. These results highlight a higher creative potential in subjects with narcolepsy and further support a role of rapid eye movement sleep in creativity.

Narcolepsy

A.M. is a 19 years old university student without any previous illness. During the fourth year of high school, episodes of motor paralysis began to occur during awakening when she is conscious, but she needs a few minutes to start to move. The episodes are manifested a couple of times monthly. Simultaneously, but rarely, there are hypnagogic hallucinations such as sound and fear in a semi awake condition and she cannot react. Practically, last three years she has attacks of irresistible sleepiness, especially when she feels comfortable. She falls asleep during lectures or when she writes a message. She sleeps for a short time during writing and that refreshes her. An 77 year-old man repeatedly experienced what he described as occasional “trance-like” states accompanied by drowsiness for about 9 years after he experienced ischemic stroke. These became increasingly frequent, finally reaching 3-5 times daily. In addition, he experienced sudden “drop attacks” during the previous 3 years. During that time, he did not receive a proper diagnosis or treatment despite several hospitalizations. Initially he was treated for epilepsy before receiving a proper diagnosis of narcolepsy.

What do we know about sleep paralysis?

Summary Introduction: Sleep paralysis (SP) is a condition that widely occurs among people all over the world. It has been known for thousands of years and is rooted in the culture of many countries. It arouses strong emotions, though still little is known about it. The clinical picture of the disorder can be very diverse. It is often accompanied by hypnopompic and hypnagogic hallucinations, somatic complaints and the feeling of intense anxiety. A feeling of paralysis in the body with inhibited consciousness is always observed with the experience. SP pathophysiology is not fully understood, however, most theories explaining this phenomenon are based on the assumption that it results from dysfunctional overlap of REM sleep and wakefulness. It is experienced by healthy people, but it is more often associated with somatic and mental disorders, which is why it is becoming an object of interest for researchers. Aim: The aim of this work is to present the most important information about the disorder known as sleep paralysis - its history, cultural context, pathophysiology, prevalence, symptomatology, coexistence with other somatic and mental disorders as well as diagnostics and available forms of prevention and treatment. Materials and methodology: The available literature was reviewed using the Google Scholar bibliographic databases searching the following keywords: sleep paralysis, REM sleep parasomnias, sleep disorder, night terrors and time descriptors: 1980-2018. Results 1. Sleep paralysis has already been described in antiquity, and interpretations related to its occurrence are largely dependent on culture and beliefs. 2. Symptomatology of the disorder is very diverse: both mental and somatic symptoms are present. 3. The pathophysiology of the disorder has not been fully explained. The basis of most theories regarding sleep paralysis is the assumption that it results from the dysfunctional overlap of REM sleep and wakefulness. 4. The prevalence of SP at least once in a lifetime is 7.6% in the general population, although it is estimated that it is much more frequent in people with various mental and somatic disorders. 5. Treatment of SP is associated with a change in lifestyle and the use of pharmacotherapy and psychotherapy.

Inner Worlds

This chapter provides an introduction to consciousness, and explores how our subjective experiences change during a variety of altered states of consciousness. An overview of cognition is given, outlining the processes involved in the construction of our experiences within the ‘stream’ or ‘theatre of consciousness’. Next, the main varieties of altered states of consciousness are discussed: psychosis, psychedelic experience, dreaming, hypnagogic hallucinations, sensory deprivation, meditation, trance, and hypnosis. Using existing dimensional models, these can be understood not as discrete states, but as points on a continuum, which significantly diverge from ‘normal waking consciousness’. For the purposes of Inner Sound, these altered states of consciousness can be represented or induced with the aid of sound and music; here an initial outline of how this may occur is given.